An opioid analgesic has a strong analgesic action and stabilizes stress reactions of circulation dynamics caused by surgical invasion. The opioid analgesic satisfies the elements of anesthesia having sedative, analgesic, and muscle relaxant actions caused by a surgical operation and keeps stresses applied to a patient during the surgical operation to the minimum, thereby restraining the extent of the stress reactions of the circulation dynamics such as the rise of a blood pressure, tachycardia, and the like caused by the surgical stresses to the minimum. From this standpoint, the opioid analgesic is suitable as an analgesic in performing general anesthesia in that the opioid analgesic surely gives ease and comfort to a patient for her/his pain after the surgical operation is performed.
Fentanyl was used as the opioid analgesic at an anesthetizing time for the past several decades. Sufentanil and alfentanil were approved as next-generation analgesics in western countries and used as the opioid analgesic at the anesthetizing time. Under such circumstances, remifentanil was approved in October of 2006 in Japan and started to be sold from January of 2007. Currently the remifentanil is used as the opioid analgesic when general anesthesia is performed.
Fentanyl is metabolized into active and nonactive metabolites in a liver, and only 10% of the metabolites is discharged from a kidney. Thus, in a case where the fentanyl is continuously medicated, it is accumulated in a body and its action remains after the medication finishes. As a result, disease symptoms such as late-onset respiratory depression, arousal delay, nausea, and vomiting appear. On the other hand, remifentanil is common with the fentanyl in that the remifentanil is a selective μ-opioid receptor agonist, but is different from the fentanyl in that the remifentanil is rapidly hydrolyzed by nonspecific esterase in blood and a living tissue and becomes the nonactive metabolite which is discharged from the kidney. The remifentanil is prompt in the appearance and disappearance of its analgesic action and does not have the property of accumulating in the body and further, is capable of easily controlling pain relief according to invasive stimulation. Because the remifentanil can be used for patients having a disorder in renal and liver functions without adjusting its capacity, the remifentanil is currently used in combination with an inhalation anesthetic and an intravenous anesthetic as an analgesic in introducing and maintaining general anesthesia (see nonpatent documents 1 and 2).
The remifentanil is soluble in water, but an aqueous solution thereof is unstable and cannot be stored for a long term. Therefore, currently lyophilized powder of the remifentanil is distributed and sold by accommodating it in containers such as a vial container.
A remifentanil injection solution to be used at an anesthetizing time is prepared by adding a large amount of water or an aqueous solution to a lyophilized remifentanil formulation. But when a large amount of water or the aqueous solution is directly added to the container accommodating the lyophilized remifentanil formulation, there occurs a danger that a remifentanil solution leaks from the container due to the rise of an internal pressure inside the container. Because the remifentanil is designated as a drug, it is necessary to perform a troublesome post-treatment when there occurs a trouble of the leak of the remifentanil solution from the container.
In consideration of the above-described problem, a method of preparing a remifentanil injection solution by performing complicated processes is proposed to administer the remifentanil injection solution to a patient at an anesthetizing time. The method includes the process of preparing a concentrate solution of the remifentanil by injecting a small amount of a dissolving solution (water, saline 5% glucose injection solution or the like) to a container such as a vial container accommodating a lyophilized remifentanil formulation to dissolve the remifentanil, the process of collecting the concentrate solution from the container, and the process of mixing a diluting solution (saline, 5% glucose injection solution or the like) with the concentrate solution to prepare a final remifentanil injection solution to be injected to the patient (see left-hand column of page 1655 of nonpatent document 1).
Normally, an anesthesiologist prepares the remifentanil injection solution by performing the above-described two-stage processes of dissolving the remifentanil in a small amount of the dissolving solution to prepare the concentrate solution and mixing the diluting solution with the concentrate solution to prepare the final remifentanil injection solution. Normally, the anesthesiologist performs the above-described complicated operation alone as a process for preparing the administration of the remifentanil injection solution. The preparation of the remifentanil injection solution required to be performed by carrying out the two-stage process may cause a risk of medication errors such as failure in adjusting the concentration of the remifentanil in the final injection solution.
In view of the above-described problems, there is a demand for the development of a remifentanil injection solution formulation which eliminates the need for performing the above-described complicated two-stage process and can be prepared by a simple operation of the anesthesiologist at a medical front, contains a correct amount of the remifentanil, and is excellent in its storage stability.
Of the opioid such as the sufentanil, an opioid high-concentration liquid medicine in which the opioid dissolves in an aromatic non-aqueous medium such as benzyl alcohol or benzyl benzoate at a high concentration of not less than 50 mg/mL is known. The opioid high-concentration liquid medicine is used to relieve pain (patent document 1). The opioid high-concentration liquid medicine of the patent document 1 is used to be continuously administered to a patient having a chronic pain for a long term, for example, several months or several years. To solve a conventional problem that the capacity of a medicine formulation is specifically limited (use of embedding pump or external pump) and that the concentration thereof is specifically limited (precipitation of medicine), the opioid high-concentration liquid medicine was developed as a 1.5 liquid medicine which can be provided without diluting the concentration thereof when a medicine having a high effective amount is needed.
To the contrary, the remifentanil injection solution is used to stabilize stress reactions of circulation dynamics caused by surgical invasion accompanied by the administration of an anesthesia and restrain sedative, analgesic, muscle relaxant actions, the rise of a blood pressure, and tachycardia caused by the surgical operation. The remifentanil injection solution is not used in combination with the inhalation anesthetic and the intravenous anesthetic. The remifentanil injection solution is different from the opioid high-concentration liquid medicine in this respect.
The aromatic non-aqueous medium such as the benzyl alcohol or the benzyl benzoate for use in the opioid such as the sufentanil and the like described in the patent document 1 has a disadvantage of being incapable of dissolving the remifentanil therein and accelerating the hydrolysis of the remifentanil. Thus, the aromatic non-aqueous medium cannot be used to prepare the remifentanil injection solution to be used at an anesthetizing time.